Complement Inhibition in Geographic Atrophy: Clinical Evidence for Pegcetacoplan and Avacincaptad Pegol

Geographic atrophy (GA) represents the advanced form of non-neovascular age-related macular degeneration (AMD) and is associated with progressive and irreversible vision loss. Evidence has implicated the dysregulation of the complement cascade as a pivotal factor in GA pathophysiology, leading to the development of complement inhibition therapies. Pegcetacoplan, a C3 inhibitor, and avacincaptad pegol, a C5 inhibitor, are currently the only therapies approved by the Food and Drug Administration (FDA) for GA secondary to AMD. Major clinical trials, including OAKS, DERBY, GALE, GATHER1, and GATHER2, have demonstrated a statistically significant reduction in GA lesion area, with reductions of approximately 16-22% for pegcetacoplan and 14-28% for avacincaptad pegol compared with sham. Despite favorable structural outcomes, functional endpoints like best-corrected visual acuity (BCVA) and low-luminance visual acuity (LLVA) have shown limited improvement, and concerns remain regarding their side effect profile. This narrative review provides an overview of GA, emphasizing its pathophysiology and the role of the complement cascade, and discusses the clinical relevance of complement inhibitors in the current management of the disease.